Selumetinib for the treatment of non-small cell lung cancer
Francesca Casaluce, Assunta Sgambato, Paolo Maione, Paola Claudia Sacco, Giuseppe Santabarbara & Cesare Gridelli
To cite this article: Francesca Casaluce, Assunta Sgambato, Paolo Maione, Paola Claudia Sacco, Giuseppe Santabarbara & Cesare Gridelli (2017): Selumetinib for the treatment of non-small cell lung cancer, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2017.1351543
To link to this article: http://dx.doi.org/10.1080/13543784.2017.1351543
Accepted author version posted online: 04 Jul 2017.
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Download by: [University of Connecticut] Date: 05 July 2017, At: 22:40
Publisher: Taylor & Francis
Journal: Expert Opinion on Investigational Drugs DOI: 10.1080/13543784.2017.1351543
Selumetinib for the treatment of non-small cell lung cancer
Francesca Casaluce, Assunta Sgambato, Paolo Maione, Paola Claudia Sacco, Giuseppe Santabarbara, Cesare Gridelli.
Division of Medical Oncology, ‘S. G. Moscati’ Hospital, Avellino, Italy
Cesare Gridelli ([email protected])
Keywords: KRAS, MEK-inhibitors, non-small cell lung cancer, selumetinib, targeted therapy.
Introduction: KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seem to remain “undruggable”, with any effective targeted therapy approved at the moment. The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supportive of KRAS testing in clinical practice of NSCLC therapy.
Areas covered: A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone. Disappointing data emerged from the next phase III trial in which the addition of selumetinib to docetaxel in patients with advanced KRAS mutant lung cancer did not improve survival or show clinical benefit.
Expert opinion: Promising strategies against this common mutation are under evaluation in clinical trials. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents, by simultaneous inhibition of the RAS– RAF–MEK–MAPK pathway. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors.
Article highlights box
•KRAS-mutant lung cancer is the largest genomically defined subset of lung cancer where no affective targeted therapy is available.
•The prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supporting the KRAS testing in clinical practice of NSCLC therapy.
•A phase II trial in KRAS-mutant NSCLC had shown significant improvements in PFS and ORR in patients treated with selumetinib plus docetaxel compared to docetaxel alone.
•In a phase III trial the addition of selumetinib to docetaxel in KRAS-mutant NSCLC did not provide a clinical benefit in terms of improving PFS or OS.
•Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumour agents by simultaneous inhibition of the RAS–RAF–MEK–MAPK pathway.
Drug summary box
•Selumetinib (AZD 6244)
•Phase I, II and III trials
•Indication: none, phase III ongoing with pending results
•Pharmacology: oral, potent highly selective MEK1/2 inhibitor
•Route of administration: 75 mg twice daily orally
•Chemical structure: C17H15BrCIFN4O3
•Pivotal trial: phase III trial (SELECT-1) in KRAS-mutant NSCLC, evaluating selumetinib plus docetaxel versus docetaxel alone as second-line treatment 
Lung cancer is the most common malignancy and the leading cause of human cancer deaths worldwide. Histology, molecular pathology, age, performance status (PS), co-morbidities and the patient’s preferences have a key role in the treatment strategies. In the last decades, several trials have consistently modified the standard approach in the first line setting, demonstrating that a novel class of tyrosine kinase inhibitors (TKIs, gefitinib, erlotinib, afatinib and crizotinib) produced higher response rates (ORR), longer progression-free survival (PFS) and an improved quality of life compared to the standard chemotherapy only in those patients with a specific molecular profile, consisting in Epidermal Growth Factor Receptor (EGFR)-sensitising mutation or in Anaplastic Lymphoma Kinase (ALK) gene rearrangements. On the other hand, in advanced Non-Small Cell Lung Cancer (NSCLC) patients with EGFR- and ALK-negative disease, chemotherapy with platinum doublets should be considered, despite a poor survival benefit. Several other oncogenes, including RAS, and their potential therapeutic role are under evaluation.
2.The KRAS oncogene: biology and epidemiology of mutational status
The KRAS gene encodes a family of membrane bound guanosine triphosphate (GTP) binding proteins, involved in several signaling cascades that regulated cell growth, differentiation and apoptosis . So, the binding of either GTP or GDP to RAS serves as the “on” or “off” switch for RAS signaling cascade, respectively. Normally, an extracellular stimuli induces an activation of RAS protein through GPT-binding, with its subsequent translocation to the plasma membrane. As active, RAS drives oncogenesis thought a multitude of effectors and downstream signaling pathways, such as RAF (MAP kinase pathway), PI3K (AKT/MTOR pathway), ERK, RLIP and
RALGDS . Finally, RAS is inactivated though its intrinsic GTP-ase activity, just that resulted lost when mutated, regardless the type of mutation. The loss of deactivating-capability of RAS mutated status sustained a dysregulation of the signaling pathways cascade, thereby leading to the aberrant cell proliferation of tumor .
The KRAS is the most frequently mutated oncogene in NSCLC, occurring in around a third of patients. However, this largest genomically defined subgroup of lung cancer patients seems to remain “undruggable”, with any effective targeted therapy approved at the moment. The KRAS mutation accounts for approximately 25% of patients with NSCLC, mostly adenocarcinoma. It was first described in lung cancer more than three decades ago, but many questions and controversies are still open.
Concerning the “targetable” EGFR-mutated lung cancers, the KRAS mutations are mutually exclusive of EGFR-activating mutations, suggesting a similar oncogenic role in lung tumorigenesis . On the other hand, the KRAS gene has been mutated in some ALK translocated cases, especially in those pretreated with an ALK inhibitor. As EGFR, a distinct clinical-pathologic subgroup of patients presented more frequently a KRAS-mutated lung cancer. The adenocarcinoma histology (30% in contrast to 5% of squamous type), the Caucasian ethnic (range of 25-50%, compared to range 5-15% in Asian patients) and a current/former smoking status have a higher probability to detect a KRAS mutated status [1, 4]. Although the association between tobacco or smoking habit and KRAS mutated status is known, some KRAS mutation subtypes are not associated with cigarette smoking. In the lung cancer of smoking patients, the KRAS mutations consist of transversions (substituting a pyrimidine for a purine or purine for a pyrimidine) more frequently than transitions (substituting purine for purine or pyrimidine for pyrimidine), with a rate of 78% and 22% respectively, unlikely KRAS mutated colorectal cancer: it might explain the discordant response to treatment between the two tumor types . In smokers, other mutations coexist with KRAS, such as those in TP53 or LKB1 (also known as SKT11), consisting in a concurrent tumor suppressor loss, and identifying a molecular signature for the smoking carcinogenesis . A recent work from The
Cancer Genome Atlas (TCGA) has shown that these co-mutations occur with similar frequency to that KRAS mutation alone in NSCLC, while a very low percentage of patients with all three simultaneous mutations .
Concerning the type of KRAS mutations in lung cancer, the exon 2 or 3 are involved in 97%, generally at codons 12 and 13 and less frequently at codon 61. The smoking-related transversion G12C is the most frequent (40%), followed by G12V (22%) and G12D (16%) . Depending on the aminoacid substitution, the activated downstream signaling is not the same, with interesting subsequent difference in terms of survival outcome. In vitro analysis from phase II trial BATTLE of lung cancer cell line phosphorylation patterns suggested that tumors harboring KRAS G12C or G12V mutations have decreased levels of phosphorylated AKT compared with other cell lines carrying other KRAS mutation, such as G12D, or wild-type (WT) KRAS, but any difference in the level of phosphorylated MEK is reported . These data suggested the greater dependency upon RAS/RAF/MEK/ERK signaling for survival of the G12C/ G12V KRAS mutated subtype tumor cell, with a potential better sensitivity to MEK inhibitors. Interestingly, the different KRAS mutations might lead not only to a different signal transduction cascades, resulting in altered drug sensitivity, but seems to have implications on survival clinical outcome: the worse median PFS was reported for patients with KRAS G12C or G12V mutations (median PFS: 1.84 months, compared to 3.35 and 1.95 months for all other mutated- and for KRAS WT, respectively) .
So, the KRAS mutant NSCLC is a very heterogeneous group, differing in term of mutational subtype, critical pathway involved and mutational subset (KRAS/TP53 or KRAS/SKT11): this might explain some of conflicting data that characterize the RAS clinical research. Further investigations are warranted to a better knowledge of all these points, for the future RAS targeted- treatment development.
Over the past two decades, a variety of drug classes have targets downstream of KRAS, but no currently available drug inhibits KRAS directly. Three major classes can be defined: first, the inhibitors of the KRAS protein synthesis, with a difficult development for drug delivery issues;
second, the inhibitors of RAS localization to plasma membrane, including the farnesyl protein transferase inhibitors, that prevent necessary post-translational modification. Despite a large number of clinical trials, their failure in the treatment of RAS mutated cancers is likely due to a compensatory prenylation of RAS . The third and last class of drugs in development is represented by a variety of agents that bypass RAS and inhibit effector molecules downstream of the mutant GTPase, including RAF-, MEK-, PI3K-, and AKT-inhibitors.
3.KRAS mutations: prognostic factor and predictive biomarker in NSCLC?
The relationship between the detection of KRAS mutations in NSCLC patients and a worse prognosis is still unclear, with disappointing data from the literature. Two early studies noted no negative prognostic value to KRAS mutations, performing biomarker analyses on tumors from 260 stage I-II and 94 stage I NSCLC patients who underwent surgical resection, respectively [10, 11]. Any prognostic role was founded also in 173 lung cancer tumors screened for RAS gene alterations: to note, a prognostic influence of the type of aminoacid substitution in the RAS protein was suggested, but a trend limited by the small patients’ population .
On the other hand, the KRAS codon-12 point mutations had a poor overall outcome and a shorter disease-free survival (DFS) despite radical resection in 69 screened lung adenocarcinoma . The detection of KRAS mutations and a related unfavorable prognosis was supported by other three studies [14-16]. To overcome biases of a retrospective design, a large prospective study was conducted to assess the association of KRAS mutation with survival . Among the 365 case patients studied for KRAS status, the codon 12 KRAS mutations were present only among subject with an history of cigarette smoking, and their detection was associated to an aggressive disease (tumors slightly higher with increasing stage), and to a worsened patient survival, but only in stage I disease .
Among KRAS exon 2, the worst prognostic value for codon 12 mutations seems to be related to different molecular profiles than codon 13. Indeed, codon 12 mutations seems to exhibit higher upregulation of VEGF production and more robust link with GTD, with decreased sensibility to GTPase activity [18, 19].
Recent publications have demonstrated that different KRAS mutations may be classified into KRAS-dependent and KRAS-independent groups and that the type of amino-acid substitution leads to differential binding affinity for downstream effector molecules . These results suggest that specific amino-acid substitutions are associated with different outcomes. However, the clinical data on resected lung NSCLC are poor and contradictory [21, 22]
An association between KRAS G12C and worsening overall survival (OS) and DFS was reported in a study of 85 patients with resected NSCLC . In contrast, a larger cohort trial identified improved OS and DFS for G12C and G12V patients in 127 patients stage I lung . However, these two studies were based on small populations, hence the limited amount of data forbids use from drawing conclusions. The largest evaluation of the prognostic value of KRAS according to amino-acid substitution has been conducted in 265 KRAS mutated resected NSCLC patients . In this trial, KRAS mutated patients experienced worse OS and DFS according to literature. However, OS and time to recurrence (TTR) rates differed according to the type of amino-acid substitution: the OS reached 62 months for G12R patients and 60 months for G12S patients; in contrast, the G12V mutation was associated with worse OS (decreasing to 26 months) and TTR (only 12 months). Furthermore, comparison of the G12V patients to the entire cohort revealed that the G12V mutation remained the only independent prognostic factor for TTR and recurrence and was associated with angioinvasion for OS .
A systematic review and meta-analysis of 28 studies was performed by Mascaux and colleagues, including a total number of 3620 patients, and showed that RAS gene alteration and/or protein p21 overexpression is a poor prognostic factor for survival of patients with NSCLC in univariate analysis, with a hazard ratio (HR) for death of 1.40 (95% confidence interval [CI], 1.18–1.65). In
the subgroups analysis according to histology, and separately according to the method of detection, the negative prognostic value of RAS alterations is observed in adenocarcinoma and when the revelation method used is polymerase chain reaction (PCR), and not immunohistochemistry (IHC) . Notably, other prognostic variables such as stage, PS, and weight loss, are not included in the multivariate analysis, because not all prognostic factors were available for all studies evaluated. Including only published trials, the HR value could be artificially elevated by a publication bias. Two more recent systematic reviews confirmed KRAS mutation as predictor for poor prognosis and treatment outcomes in NSCLC [25, 26]. In the first one, including 41 trials (6939 patients), KRAS mutations are associated with a worse OS in patients with NSCLC, especially in patients with adenocarcinoma (HR:1.39; 95% CI: 1.24-1.55) and early stage (HR for stage I: 1.81, 95% CI: 1.36- 2.39; HR for stage I-IIIA: 1.68; 95% CI: 1.11-2.55) . The negative prognostic role of KRAS mutation was confirmed in the second meta-analysis of 41 trials (13103 patients) reporting worse OS and DFS in early stage resected NSCLC (HR=1.56 and 1.57, 95% CI 1.39-1.76 and 1.17-2.09 respectively) .
In conclusion, KRAS could be a prognostic negative biomarker, but the optimal approach to determine it is to obtain KRAS mutation status prospectively as part of a clinical trial. The only and first reported large trial that prospectively assessed KRAS mutations was conducted as part of E3590, a randomized intergroup trial of postoperative adjuvant therapy (radiotherapy alone or concurrently with chemotherapy) in patients with completely resected stage II-IIIA NSCLC . Of the 488 patients who enrolled in E3590, tumors from 197 were available for KRAS mutational analysis, and mutations were identified in 24%. No correlation between the presence or absence of KRAS mutation and OS or PFS was observed, although there was a trend toward improved survival for patients with KRAS WT compared with KRAS mutated on the chemotherapy arm of the study (median OS: 42 and 25 months, respectively; p: 0.09). Furthermore, in the multivariate analysis, KRAS mutation was not an independent prognostic factor, suggesting that KRAS mutation did not carry a distinct prognosis in this sample of patients with resected NSCLC .
Several trials have evaluated the clinical usefulness of KRAS mutation status in predicting response to treatment, showing a lack of benefit from EGFR-TKIs and a reduced benefit from adjuvant chemotherapy, thought the universally of this concept is now being questioned.
The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of signaling from the EGFR, possibly rendering a tumor resistant to therapies that target the EGFR, as emerged from metastatic colon rectal cancer trials. In the targeted era, the best knowledge of KRAS status as predictive biomarker for EGFR-TKIs therapy should be worthy of further research, considering its potential key role in the treatment strategy of metastatic EGFR mutated NSCLC patients.
After inconclusive epidemiologic trials, a meta-analysis was performed, including 22 trials, with a total of 1470 NSCLC patients, of whom 231 had KRAS mutations (16%), commonly smokers and adenocarcinoma . Despite the sample’s heterogeneity, this analysis showed that the KRAS mutations were associated to a resistance to EGFR-TKIs treatment (gefitinib or erlotinib) in NSCLC patients, reporting a higher response rate in KRAS WT than mutated patients (ORR: 26% versus 3%, respectively) . From subgroup analyses conducted on the basis of ethnicity, the predictive negative role of KRAS was more robust in Asian than Caucasian population, underlying the interethnic differences for EGFR pathway activation. In the subgroup analysis for study treatment, the smoking status might be a confounding variable in the erlotinib group, considering that KRAS mutated patients are generally current smokers, with known pharmacokinetics difference of the erlotinib, less effective for the increased metabolic clearance .
The BR.21 placebo controlled trial showed erlotinib to be effective in advanced NSCLC patients unable to tolerate further treatment after receiving at least one platinum-based doublet. A significant effect of KRAS genotype on the response to erlotinib was reported, confirming better results for patients with KRAS WT, in term of activity (ORR 10% versus 5%, p: 0.69) as well as survival
benefit (HR: 0.69 vs. HR: 1.67) . However, the multivariate analysis confirmed only EGFR fluorescent in situ hybridization (FISH) as the strongest prognostic marker and a significant predictive marker of differential survival benefit from erlotinib.
Concerning erlotinib as maintenance strategy in metastatic NSCLC patients, not progressing after first-line chemotherapy, the phase III placebo-controlled trial named SATURN (Sequential Tarceva in Unresectable NSCLC), showed longer PFS with erlotinib irrespective of KRAS mutational status . On the other hand, the ATLAS trial showed a significant improvement in term of PFS in the maintenance arm of bevacizumab plus erlotinib compared to bevacizumab alone (4.8 vs. 3.7 months, HR: 0.722); from subgroup analysis of KRAS status, the PFS benefit was confirmed only for patients with KRAS WT .
In the Trial Evaluating REsponse and Survival versus Taxotere (INTEREST), gefitinib was shown to be equivalent to docetaxel as second-line therapy, but with improved quality of life, and no differences were detected between two arms according to KRAS status .
In the French prospective ERMETIC trail, EGFR and KRAS were studied by sequencing DNA from 522 metastatic NSCLC patients treated with an EGFR-TKIs mostly in second- or third-line settings, and reporting a similar rate of EGFR and KRAS mutations (14%). The EGFR and KRAS status independently impacts outcomes in advanced NSCLC treated with EGFR-TKI: EGFR status impacts both PFS and OS, whereas KRAS only impacts OS .
Poorly understood is the benefit of chemotherapy as adjuvant and as first-line treatment in KRAS mutated NSCLC patients. In contrast to the numerous studies on prognosis, data on the predictive value of RAS in early stage NSCLC patients treated by adjuvant chemotherapy are lacking. The retrospective analysis from JBR10 did not find a significant benefit in 117 KRAS mutated patients treated with adjuvant chemotherapy adjuvant (cisplatin plus vinorelbine) compared to observation (HR: 0.95, p=0.87), in contrast to significantly prolonged survival in 333 patients with RAS WT (HR: 0.69, p=0.03) . However, in the Cox model, significant interaction between chemotherapy and RAS mutation was not detected (p=0.29), not confirming the KRAS predicting role.
Subsequently, the international collaborative BIO-LACE (Biomarkers-Lung Adjuvant Cisplatin Evaluation) study undertook a pooled analysis of KRAS mutation in four different trials of adjuvant chemotherapy (ANITA, JBR.10, IALT, CALGB-9633) versus observation to clarify its prognostic/predictive roles in this setting of resected NSCLC patients . Mutation results from 1543 patients identified KRAS mutated in 300 specimens (19%), generally codon 12 mutations (275 patients), infrequent codon 13 (24 patients), and only one codon 14 mutations. From this analysis, KRAS mutation status was not significantly prognostic, and no significant benefit from adjuvant chemotherapy resulted, with a detrimental effect in patients carrying the KRAS codon 13 mutations (HR: 5.78, p=0.001). Although statistically significant, this result must be interpreted with caution and require validation, considering the small simple size of only 24 patients .
In the metastatic setting, several studies have examined the correlation between KRAS mutations and chemotherapy’s benefit, with mixed data [37-40]. The first retrospective study analyzed the prognostic and predictive value of KRAS mutations among 484 patients, with KRAS and EGFR mutation information available (39 patients with KRAS mutations and 182 patients with EGFR mutations). The multivariate analysis evidence KRAS mutation as a poor prognostic factor (HR: 2.6), and its presence predicted for worse response to gemcitabine-based or pemetrexed-based chemotherapy (RR: 14 % and 28%, in KRAS mutated and KRAS WT, respectively) . A second larger trial confirmed KRAS as marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced non-squamous EGFR WT NSCLC. The 77 patients carrying a KRAS- mutant phenotype experienced a significantly inferior outcome in terms of response rate (p: 0.04), DCR (p=0.05), and PFS (p=0.05) were reported compared with the EGFR WT/KRAS WT population . Recently, a larger Caucasian study reported no mutation-related significant differences in either PFS (p: 0.534) or OS (p: 0.917) among 505 known KRAS status patients (338 KRAS WT; 147 KRAS codon 12 mutant; 20 KRAS codon 13 mutant) treated with platinum-based chemotherapy . Notably, patients with G12V KRAS mutant adenocarcinomas (more frequent among never-smokers) not only tended to respond better to platinum-based chemotherapy
(p=0.077) but, although non-significantly, were also more likely to have a longer PFS (p=0.145) than those with other codon 12 mutations . This finding is in line with a recent in vitro study in which Garassino and colleagues found strong differences in treatment response to cisplatin among KRAS overexpressing clones of human lung adenocarcinoma cells (NCI-H1299) with different amino acid substitutions, reporting better responses in G12V mutant cells, with the least response in the most common G12C transversion mutant cells . In particular, the expression of G12C is associated with a reduced response to cisplatin and an increased sensitivity to paclitaxel and pemetrexed, whereas the expression of G12D mutant resulted in resistance to paclitaxel treatment and sensitivity to sorafenib. The G12V mutant showed a strong sensitivity to cisplatin when compared with the WT clones and was slightly more resistant to pemetrexed. In contrast, the expression of different KRAS mutants did not modify the cellular response to erlotinib and to gemcitabine . Even more interesting are data from the first completed prospective biomarker- based phase II trial, known as the BATTLE trial, in which 255 pretreated lung cancer patients were adaptively randomized to four testing arm (erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib) based on relevant molecular biomarkers . Although no correlation between survival benefit and KRAS status was showed, independently of the treatment arm (considering the impressive benefit from sorafenib among KRAS mutant patients) the presence of two specific mutations in KRAS codon 12 (G12C or G12V) was related to a worse PFS, compared to other subtype of mutation and with KRAS WT .
Finally, the type of KRAS aminoacid substitution could affect the responsiveness to radiation therapy. From a multivariate analysis of retrospective trial focusing on 157 NSCLC patients with EGFR/ KRAS testing and treated with brain radiotherapy, the KRAS G12V or G12C status was associated with both poor response rate and OS .
Furthermore, an interesting positive correlation between the presence of a KRAS mutation and radiosensitization by EGFR inhibitors erlotinib and cetuximab was reported in preclinical studies,
identifying EGFR as a potential molecular target to overcome a novel mechanism of radioresistance in KRAS mutant tumor cells .
In conclusion, the prognostic and predictive power and thus the clinical utility of KRAS oncogenic mutations in lung cancer are highly debated issues, not supporting the KRAS testing in clinical practice of NSCLC therapy. A major obstacle to draw a definitive conclusion is the vast heterogeneity of the studies in terms of ethnicity, histological subtype, tumor stage and treatment modality. On the other hand, the literature data are available generally from retrospective analyses, with their intrinsic limitations. At present, the KRAS mutation testing find a role as initial screening for EGFR and ALK analysis, due to the mutually exclusive appearance of these two mutations. However, the fascinating hypothesis that different RAS mutations may lead to a different signal transduction cascade in NSCLC, and subsequently to a different carcinogenesis and drug sensitivity, should drive the future direction of research. These data might be important clinical implications, and if confirmed, the simple definition of KRAS mutated tumor could not be enough (without the definition of the specific mutation present) to identify patients with a different probability of responding to therapy in lung, as previously in colon cancers. Nevertheless, additional large international collaborative group are required.
4.Selumetinib: from preclinical to clinical trials
Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, inhibitor of MEK1/MEK2 kinases. MEK inhibition by ARRY-142886 is not competitive with respect to ATP. The binding of ARRY-142886 to the allosteric inhibitor binding site in MEK1/2 is proposed to lock MEK1/2 into an inactive conformation that enables binding of ATP and substrate but disrupts both the molecular interactions required for catalysis and the proper access to the ERK activation loop .
AZD6244 has an excellent preclinical activity against many different tumors in cell-based growth assay and in human tumor mouse xenograft models. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harbouring BRAF or RAS mutations were more likely to be sensitive to AZD6244. In vitro sensitivity broadly predicts in vivo efficacy, resulting in suppression of growth of nude mice bearing xenografts from cells with BRAF or KRAS mutations . AZD6244 was able to potently inhibit basal ERK1/2 phosphorylation, the unique substrate of MEK, and p-ERK has been validated as a robust biomarker of AZD6244 activity in human tumor xenografts growing in nude mice. Moreover, 25 mg/kg bid AZD6244 in combination with either 15 mg/kg docetaxel or 25 mg/kg irinotecan resulted in significantly enhanced antitumor activity than the same dose of either agent alone in mice bearing SW-620 xenografts (sensitive to the cytotoxic drugs docetaxel and irinotecan). A statistically significant interaction occurs between docetaxel and AZD6244 at these doses (p = 0.02), indicating a synergistic effect, whereas no significant interaction occurs between irinotecan and AZD6244 at these doses, indicating an additive effect (p = 0.68) .
Results of additional preclinical in vivo studies have shown that the combination of selumetinib and docetaxel leads to greater tumour-growth inhibition or regression, and apoptosis [47, 48]. Holt et al. combined selumetinib with temozolomide (DNA-alkylating agent) in human xenograft models, reporting an enhanced tumour growth inhibition compared with monotherapies . Biomarker studies highlighted an increase in gH2A.X suggesting that selumetinib is able to enhance the DNA damage induced by temozolamide alone. Moreover, the continuous exposure to selumetinib in combination with docetaxel results in tumor regression in several models. Scheduling of docetaxel before selumetinib was more beneficial than when selumetinib was dosed before docetaxel and demonstrated a pro-apoptotic phenotype. Similar results were seen when selumetinib was combined with the Aurora B inhibitor barasertib . At last, selumetinib has been shown in preclinical study to be effective when combined also with targeted agents such as VEGF receptor tyrosines kinases (cediranib), mTOR and AKT inhibitors [48-50].
4.2Phase I trials
Given this spectrum of preclinical activity and the acceptable toxicology profile, a phase I study was undertaken to evaluate the safety, tolerability (part A, dose-escalation part), pharmacokinetics (PK), and pharmacodynamics (PD, part B) of AZD6244 in patients with advanced malignancies . Fifty-seven patients (35% malignant melanoma; 17.5% breast, 8.8% colorectal and 38.6% other malignancies) received a total of 184 assessable cycles of therapy across four dose levels (50, 100, 300, and 300 mg bid). Maximum-tolerated dose (MTD) in part A was 200 mg bid, but the lower dose level (50% of the MTD; 100 mg bid) was recommended as the tolerable phase II dose because of an increase in the frequency and severity of rash in part B. Rash (dose dependent, erythematous, and maculopapular, occurring predominantly on the torso) was the most frequent and dose-limiting toxicity (DLT) occurring in 74% of all patients. Most other adverse events (AEs; diarrhoea, nausea, and fatigue) were grade 1 or 2. A transient and reversible blurred vision has been reported in seven patients. Five of these ocular events were observed at doses greater than the recommended phase II dose. Ophthalmologic examinations were unrevealing in regard to etiology. The PKs were less than dose proportional, with a median half-life of approximately 8 hours. The PK profile supports a bid dosing scheme that results in exposures that adequately inhibit the drug target. Even if skin biopsies were generally uninformative due to the variable and minimal baseline levels of pERK, a dose-dependent inhibition of ERK phosphorylation in peripheral-blood mononuclear cells (PBMCs) at all dose levels was reported, as well as consistent inhibition of ERK phosphorylation when comparing pre- and post-treatment tumor biopsies. However, data were insufficient to suggest a correlation between surrogate tumor tissue PD. The best clinical response was stable disease that lasted for 5 or more months in nine patients. Two patients maintained stable disease for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles . Previous phase I trial of AZD6244 used a liquid suspension that established a proof of concept but would not be practical for long-term twice-daily dosing. Another two-part phase I study evaluated the safety, PK, and PD of the new formulation AZD6244 hydrogen sulfate capsule in patients with
advanced cancers (30 patients in part A: dose-escalation; 29 patients in part B: randomization single dose Hyd-Sulfate capsule or free-base suspension) . The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events (CTCAE) grade 3 acneiform rash and pleural effusion. The safety profile of the 75 mg twice-daily Hyd-Sulfate capsule was consistent with that of the 100 mg twice-daily free-base suspension. The most common AEs were fatigue, acneiform dermatitis, nausea, and diarrhoea, similar to that previously reported for the AZD6244 free-base suspension at MTD . The new formulation reported a plasma exposure (Cmax and AUC0-24) statistically significantly higher than that for the 100 mg free-base suspension and caused a time-dependent suppression of pERK, with the magnitude of suppression being generally related to drug plasma concentrations. The best clinical outcome was a prolonged complete response in malignant melanoma with V600E BRAF mutation .
A phase I study was performed in order to assess the safety, tolerability and PK of escalating doses of selumetinib in combination with different agents, including docetaxel, in 140 patients with advanced solid tumors and define the MTD of selumetinib in these combinations . Of these 140 patients, 35 received selumetinib combined with docetaxel: the recommended phase II dose (RP2D) of selumetinib combined to docetaxel (75mg/m2 three weekly) is 75mg BID, with the addition of granulocyte colony stimulating factor (GCSF) in heavily pre-treated patients. The combination treatment AE profile was largely consistent with selumetinib or docetaxel monotherapy. The most common AEs were peripheral edema, diarrhoea, fatigue, nausea, vomiting, neutropenia, and dermatitis acneiform. Haematological events, infections, fatigue/asthenia, peripheral edema, and gastrointestinal events were the most common grade ≥3 AEs. Responses were observed in 5/28 pts (18%) receiving selumetinib 75 mg bid + docetaxel +/- GCSF in this non-comparative study .
Two phase I trials have investigated selumetinib in combination with chemotherapy as first-line treatment. In the first, selumetinib has been tested in combination with platinum-doublet
chemotherapy for patients with advanced NSCLC (unselected for KRAS mutation status) . Fifty-five patients (38 adenocarcinoma and 13 squamous) were enrolled into dose-finding cohorts of selumetinib (50 mg, 75 mg or 100 mg bid orally) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. The RP2Ds were identified as selumetinib 75 mg bid plus standard doses of pemetrexed and carboplatin or pemetrexed and cisplatin, with AE profiles consistent with the individual agents. Most frequent AEs were fatigue, nausea, diarrhoea and vomiting. The RP2Ds were not determined for gemcitabine-based regimens. Preliminary anti- tumour activity was observed across all cohorts: confirmed partial responses were observed in 11 (20%) patients and unconfirmed in 9 (16%) patients, and 21 (38%) patients had stable disease (≥6 weeks) .
The second phase Ib study tested continuous or intermittent selumetinib [dose level 1 (DL1): 50mg bid d2-19, DL2: 75 mg bid d2-19, DL3: 75 mg bid d1-21 (continuous) with either carboplatin/paclitaxel (cohort 1) or cisplatin/pemetrexed (non-squamous, cohort 2) or pemetrexed alone (cohort 3) in 30 previously untreated NSCLC . Preliminary data of cohort 1 and cohort 2 reported that selumetinib can be given in combination with either platinum-based chemotherapy at full single agent doses, with generally mild incremental gastrointestinal and skin toxicity. Data about RP2D expansion cohorts at a dose of 75 mg bid d1-21 are still pending .
Multiple phase I studies are evaluating the combination of selumetinib with targeted agents. Vandetanib, a dual EGFR/VEGFR inhibitor, and selumetinib have overlapping toxicities, yet the combination has been manageable, with the AE profile consistent with the known monotherapy profiles (higher incidence of reversible eye events in combination) in solid tumors . Selumetinib dose of 100 mg once daily or 50 mg twice daily is the MTD in combination with vandetanib, while vandetanib combination MTD to be confirmed. Stable disease was confirmed in four NSCLC patients who received 6-10 cycles: an expansion cohort in NSCLC is ongoing with anti-tumor efficacy endpoint (NCT01586624).
An open-label, non-randomized, multicenter phase Ib/II study (a phase Ib dose escalation part and a phase II dose expansion part) is testing selumetinib in combination with gefitinib 250mg daily in EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment (NCT02025114).
TATTON is a multi-arm phase Ib trial investigating osimertinib 80 mg (third-generation EGFR- TKI) in combination with durvalumab (a selective, high-affinity human IgG1 mAb, that blocks PD- L1 binding to PD-1 and CD80), savolitinib (MET inhibitor) or selumetinib in patients with advanced EGFR-mutant lung cancer . Forty-four patients have been enrolled on combination therapy (21 in selumetinib). In the selumetinib arm, one DLT of transaminase elevation has been reported and 2 partial responses have been observed .
Preclinical studies suggested that selumetinib may prime the immune response and also potentially inhibit T-cell function, thereby maximizing tumor cell damage and antigen presentation during the period of MEK inhibition; intermittent dosing with selumetinib will allow maximal relief of T-cell checkpoint blockade by durvalumab . Based on these evidences, selumetinib in combination with durvalumab is under evaluation in the SELECT-4 study. SELECT-4 is a phase I dose escalation study investigating the safety and tolerability of intermittent doses of selumetinib (starting dose 50 mg orally bid, increasing until the MTD is reached, given for a 7-day monotherapy run in, then on a 1 week on, 1 week off schedule, every 4 weeks) combined with durvalumab (1500 mg intravenously once every 4 weeks) for the first time in patients with advanced solid tumors for which no standard therapy exists. Approximately 20–30 evaluable patients will be enrolled, with up to 6 patients in each dose escalation cohort and 6–10 evaluable patients in a paired biopsy expansion cohort .
One possible mechanism of resistance to selumetinib in NSCLC patients is activation of PI3K pathway. A high level of AKT activation is associated with the resistance to MEK inhibitor while dual inhibition of the AKT and ERK pathways increased the antitumor activity of selumetinib. A dose/schedule-finding phase I study evaluating MK-2206 (AKT inhibitor) and selumetinib in
patients with advanced treatment-refractory solid tumors has been conducted. Grade 3 rash was the most common DLT; other DLTs included lipase increase, stomatitis, diarrhoea, and fatigue. Clinical antitumor activity included RECIST 1.0–confirmed partial responses in NSCLC and low- grade ovarian carcinoma .
AZD2014 is a drug that blocks a protein called mTOR that is involved in the growth and spread of cancer. Blocking the action of either MEK or mTOR alone may slow down or stop the cancer growing. Combining both drugs may make the cancer more sensitive than if selumetinib or AZD2014 are used alone, leading to increased anti-tumour effects. The ongoing phase 1b (Dose Escalation Phase) will determine what the recommended dose to use in Phase IIa (Dose Expansion Phase) will be (NCT02583542) (Table 1).
4.3Phase II trials
A subsequent phase II trial evaluated the efficacy and safety of 100 mg selumetinib free-base suspension twice daily versus pemetrexed as second- or third-line treatment in 84 patients with advanced NSCLC, non-selected for KRAS mutation . Selumetinib did not demonstrate superiority to pemetrexed in terms of efficacy with a median PFS (primary end point) not statistically different (67 vs. 90 days, respectively; HR: 1.08, two-sided 80% CI 0.75–1.54; p=0.79). Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the selumetinib and pemetrexed groups, respectively (HR: 1.35; two-sided 80% CI 0.93–1.94; two-sided 95% CI 0.77–2.36; p=0.30). Response rates were also similar in both arms (5.0% vs. 4.5%, respectively). Two patients in the selumetinib group had a best response to treatment of partial response. Of note, patients treated with pemetrexed were not selected for histology (the study did not exclude squamous histology) therefore the activity of pemetrexed in the non-squamous population may be underestimated. As well as pemetrexed, patients have not been selected for BRAF or RAS gene mutations that demonstrated in vitro a tendency toward sensitivity to selumetinib. Dermatitis acneiform (43%), diarrhoea (30%), nausea (18%), and vomiting (18%) were the most frequently
reported AEs with selumetinib, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed .
Based on preclinical data suggesting that selumetinib is most effective in patients with KRAS- mutant NSCLC, a prospective randomised phase II trial evaluated the efficacy and safety of selumetinib in combination with docetaxel as second-line treatment for KRAS-mutated NSCLC patients . Of a total of 422 patients screened, 87 patients were randomly assigned, in a 1:1 ratio, to receive docetaxel 75 mg/m2 three-weekly in combination with either selumetinib hydrogen sulphate capsules 75 mg bid (selumetinib group: 44 patients) or placebo (placebo group: 43 patients). Although there was no significant difference between two groups in the median OS (primary end point), selumetinib treatment was associated with significant improvements in PFS, ORR, and patient-reported outcomes. Median OS was 9.4 and 5.2 months in the selumetinib group and placebo group respectively, representing a non-significant 20% reduction in risk for death with selumetinib (HR for death: 0.80; 80% CI 0.56–1.14; one-sided p=0.21). Median PFS was 5.3 and 2.1 months in the selumetinib group and placebo group respectively, representing a significant 42% reduction in risk for progression (HR for progression: 0.58; 80% CI 0.42–0.79; one-sided p=0.014). Objective response was significantly more common with the combination than docetaxel alone (37% vs. 0%, p<0.0001). All responses were partial responses and the median duration of response was 182 days. The improved outcomes with selumetinib plus docetaxel were associated with an increase in AEs and serious AEs relative to placebo and docetaxel. The most frequent AEs of any grade in the selumetinib group were neutropenia, diarrhoea, nausea, vomiting, peripheral oedema, rashes, and stomatitis. The proportion of serious AEs was higher in the selumetinib group than in the placebo group (82% vs. 67%, respectively). Grade 3–4 neutropenia (67% vs. 55%), febrile neutropenia (18% vs. 0), and asthenia (9% vs. 0) were more common in the selumetinib group than in the placebo group; by contrast, grade 3–4 dyspnoea (2% vs. 12%) was more common in the placebo group than the selumetinib group. Serious AEs occurred in 59% of selumetinib patients and 31% of placebo patients: the most common were febrile neutropenia (14% vs. 0%), pneumonia (9%
vs. 0%), neutropenia (7% vs. 7%), and respiratory failure (7% vs. 5%). The number of AEs leading to death was low in both groups (9% in selumetinib group and 7% in placebo group) .
Based on the hypothesis that KRAS G12C or G12V mutations predict for better response to selumetinib plus docetaxel compared with other KRAS mutations, a retrospective analysis of the impact of different KRAS codon mutations or combinations of codon mutations on efficacy outcomes (OS, PFS change in tumour size at week 6 and ORR) in the previously reported phase II trial has been performed . The KRAS mutation groups (MGs) assessed were: MG1 (KRAS G12C or G12V); MG2 (all KRAS mutations other than G12C or G12V). The most common KRAS mutation were G12C (46%), G12D (22%), and G12V (11%). In patients receiving selumetinib in combination with docetaxel and harbouring KRAS G12C or G12V mutations (MG1 group) there were trends towards greater improvement in OS, PFS and ORR (but no change in tumor size at week 6) compared with other KRAS mutations. Of note, these trends are weak and not statistically significant. The small number of patients analysed in this phase II trial means it is underpowered for this analysis, larger clinical studies would be required to test robustly the hypothesis that specific codon status can condition response to therapy .
SELECT-2 is another double-bind randomized three arm phase II trial that is exploring two different doses for docetaxel (75 mg or 60 mg/m2) in combination with selumetinib compared to docetaxel alone in order to understand the tolerability profile of the different dosing regimens in these patients. Recruitment is complete with pending results (NCT01750281).
The combination therapy of selumetinib and erlotinib was hypothesized to potentially improve clinical efficacy in both KRAS mutant patients and KRAS WT patients by a more profound blockade of the RAS/RAF/MEK/ERK signalling pathway. This strategy has been investigated in a randomized phase II trial enrolling 89 pretreated patients with advanced NSCLC divided into two groups based on KRAS profiling: 41 KRAS WT patients were randomized to erlotinib (150 mg daily) or a combination of selumetinib (150 mg daily) with erlotinib (100 mg daily); 38 KRAS mutant patients were randomized to selumetinib (75 mg bid) or the combination . This study
failed to show improvement in ORR or PFS with combination therapy regardless KRAS status. Furthermore, the combination therapy resulted in increased toxicities, requiring dose reductions (56%) and discontinuation. The lack of efficacy of dual inhibition of the EGFR and MEK components may be secondary to the potential increased activation of the PI3K/AKT pathway or induced MEK reactivation by CRAF (Table 1) .
4.4Phase III trials
Despite observing a significant improvement in PFS and response with the MEK1/2 inhibitor combination in an earlier phase II study , the eagerly awaited first prospective phase III trial (SELECT-1) in KRAS-mutant NSCLC, evaluating selumetinib plus docetaxel versus docetaxel alone as second-line treatment, has failed to meet its primary endpoint of improvement in PFS . Of a total of 3323 patients screened, 510 patients with a centrally confirmed KRAS mutation were randomised 1:1 to oral selumetinib (75 mg bid) plus intravenous docetaxel (75mg/m2 three-weekly; n=254), or docetaxel plus placebo (n=256). All patients received pegylated GCSF at least 24 hours after each docetaxel dose to address the toxicity observed in the phase II trial. At data cut-off, median PFS was not significantly different between the selumetinib arm and placebo arm (3.9 months vs. 2.8 months, HR 0.93, 95% CI 0.77–1.12; p=0.44). Similarly, the combination did not show a significant effect on OS (8.7 months vs. 7.9 months, HR 1.05, 95% CI: 0.85, 1.30; 2-sided p=0.64), while a trend towards a higher ORR was observed with selumetinib compared with placebo (20.1% versus 13.7%; odds ratio: 1.61; 95% CI: 1.00, 2.62; 2-sided p=0.051). The safety profile was consistent with historical data. The selumetinib plus docetaxel combination was associated with a higher incidence of AEs (all causality: 99% vs. 95% patients in placebo group) and grade ≥ 3 AEs (67 vs 45% patients in placebo group). Serious AEs occurred more frequently in patients treated with the combination compared to docetaxel arm (49% vs. 32%, respectively), as did adverse events leading to hospitalisation (46% vs. 30%, respectively) (Table 1) .
CUSTOM (Molecular Profiling and Targeted Therapies in Advanced Thoracic Malignancies) study is the first completed basket clinical trial to identify molecular biomarkers and determine their frequency and clinical relevance in patients with multiple histologic subtypes concurrently (advanced NSCLC, SCLC, and thymic malignancies) and to evaluate the efficacy of multiple targeted therapies in specific molecular subsets of patients . The five targeted therapies included erlotinib (EGFR mutations); the MEK inhibitor selumetinib (KRAS, HRAS, NRAS, or BRAF mutations); MK2206, an AKT inhibitor (PIK3CA, AKT1, PTEN mutations); lapatinib (HER2 mutations); and sunitinib (KIT, PDGFRA mutations). The protocol design is allowed enrolment of patients with multiple histologic subtypes, a non-specified number of previous therapies, and any organ function or PS onto the molecular profiling portion of the study. A total of 647 patients were enrolled, and 88% (n=569) had their tumors tested for at least one gene. The trial was powered to identify an ORR of 40% in patients whose treatment was selected based on molecular alterations. Of the 110 patients with RAS/RAF mutations, 11 patients (10 with NSCLC and one with SCLC) were enrolled onto the selumetinib treatment arms. In nine evaluable patients with NSCLC, selumetinib monotherapy failed to achieve its primary end point, with an ORR of 11%, a median PFS of 2.3 months, and median OS time of 6.5 months. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved an ORR of 60% (n=15 NSCLC patients treated). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years), followed by those with ALK rearrangements (2.94 years), those with KRAS mutations (2.3 years), those with other genetic abnormalities (2.17 years), and those without an actionable mutation (1.85 years) . One possible explanation of these data could be that targeting MAP kinase signaling in KRAS-mutant lung cancers may depend on additional genetic aberrations (such as loss of key tumor suppressors) that might be involved in the response of selumetinib treatment .
By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in NSCLC established by the BATTLE trial, BATTLE-2 (BATTLE-2 Program: A Biomarker-
Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer) study evaluated the effects of targeted therapies focusing on KRAS-mutated cancers. Two hundred pretreated NSCLC patients (27% with KRAS-mutated; EGFR sensitizing mutations or ALK gene fusions were excluded) were randomly assigned, stratified by KRAS status, to four arms: erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). The trial data demonstrated the following key points: there was no significant association between 8-week DCR and KRAS mutation status; patients with KRAS WT tumors treated with erlotinib-containing therapy had better OS compared with those treated with therapy that did not contain erlotinib, whereas patients with KRAS mutated tumors experienced longer PFS if treated with therapy that did not contain erlotinib and better 8-week DCR with MEK and AKT inhibitor therapy; and mesenchymal gene signature was associated with improved OS (Table 1) .
KRAS mutation is the most common oncogene driver mutation in patients with NSCLC and confers a poor prognosis in the metastatic setting making it an important target for drug development. The RAF-MEK-ERK (MAPK) pathway subsequently activated is quite complex and multiple strategies have been proposed to target this mutation. Although KRAS mutations were identified in lung nearly 20 years ago, to date, an effective agent to KRAS mutant NSCLC remains elusive. Unlike ALK and EGFR mutations, no targeted therapy is still available for KRAS mutated patients. Currently, promising strategies against this common mutation are under evaluation in clinical trials, such as trametinib and selumetinib in combination with chemotherapy. Among novel molecular therapeutic targets and markers under investigation, the place of micro-RNAs is steadily growing .
The different immune checkpoints expression in oncogene-addicted NSCLC - higher levels of PD-1 expression detected in KRAS mutated population – might represent the rationale to choose a
different checkpoint inhibitor according to the tumor driver, but prospective data are warranted .
KRAS-mutant lung cancer is the largest genomically defined subset of lung cancer where no affective targeted therapy is available. To date, the KRAS testing in clinical practice of NSCLC therapy is not supported because its role is limited predominantly to a negative prognostic factor. However, the fascinating hypothesis that different RAS mutations may lead to a different signal transduction cascade in NSCLC, and subsequently to a different carcinogenesis and drug sensitivity, should drive the future direction of research.
Selumetinib significantly suppressed tumour growth in preclinical data from KRAS-mutant NSCLC tumour xenografts. Early phase clinical studies of selumetinib as single agent showed target inhibition and tumor responses, confirming a little clinical activity also in unselected pretreated NSCLC population enrolled in a phase II trial. In terms of combination strategies, additional preclinical in-vivo studies showed greater tumour-growth inhibition or regression, and more apoptosis when selumetinib was added to docetaxel, with a synergistic effect. After manageable tolerability profile emerged from a phase I study, the addiction of selumetinib to docetaxel improved significantly PFS and ORR in K-RAS mutant NSCLC patients treated in a phase II trial. Disappointing data emerged from the next phase III trial in which this combination used in the same setting of patients (KRAS mutant advanced NSCLC), which does not provide evidence of clinical benefit. This negativity could be explained from the very small sample size of the randomized phase II study on which the subsequent phase III trial design was based.
Similarly, a randomized phase II trial the combination of another MEK inhibitor (trametinib) and docetaxel failed to show any difference in efficacy for NSCLC, regardless of KRAS mutational status.
The successful development of MEK inhibitors is limited by the complexity of RAS–RAF–MEK– MAPK pathway, its interaction with other different pathways and the early development of
resistance mechanisms. Combination therapies represent a potential approach for overcoming this complex pathway and potentiating the activity of other antitumor agents by simultaneous inhibition of the RAS–RAF–MEK–MAPK pathway. The dual blockade of RAS–MEK–ERK cascade has proven successful using the combination of the MEK inhibitor trametinib and the BRAF dabrafenib for the treatment of BRAF mutant metastatic melanoma, leading to recent approval by the United States Food and Drug Administration (US FDA). This rationale might be applicable to NSCLC, potentially providing one mechanism to prolong clinical benefit and overcome resistance. A number of combination therapies incorporating MEK inhibitors are being tested in clinical trials, but such therapeutic approaches have been hampered by toxicity issues, which prevent the use of adequate doses of MEK inhibitors. Identifying predictive biomarkers, and delineating de novo and acquired resistance mechanisms are essential for future clinical development of MEK inhibitors.
Hence, these remain a desperate need and an opportunity to develop new treatments for this subset of NSCLC.
This paper was not funded.
Declaration of Interest
C Gridelli has received honoraria as speaker bureau and advisory board member for Bristol Myers Squibb, MSD, Pfizer, Roche, Novartis, Astra Zeneca, Eli Lilly and Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from
Table 1. Ongoing clinical trials on selumetinib in NSCLC
Patients Primary end point
I Combined to standard chemotherapy
Advanced solid tumors
211 Safety and tolerabilit y Ongoing, not recruiting
I Combined to standard chemotherapy Advanced NSCLC
MTD Ongoing, not recruiting
I Combined to PTX Second-line – not selected
Combined to vandetanib Solid Tumours (Dose Escalation) and NSCLC (Expansion Cohort)
Combined to AZD9291 EGFR- mutated EGFR-TKI resistant
I Combined to MEDI4736 Advanced solid tumors 40 AE Recruiting NCT02586987
I Thoracic Radiotherapy Advanced NSCLC 33 RP2D Recruiting NCT01146756
Combined to gefitinib EGFR- mutated EGFR-TKI resistant
I//II Combined to AZD2014 Advanced solid tumors 118 DLT Recruiting NCT02583542
Combined to afatinib Advanced KRAS Mutant and PIK3CA WT Colorectal, NSCLC and Pancreatic Cancer
II Combined to KRAS WT 89 PFS Ongoing, NCT01229150
erlotinib – KRAS mutant not recruiting
II Combined to TXT Second-line – not selected
PFS Ongoing, not recruiting
Combined to PEM+platinum
-based KRAS WT/
Unknown Non- Squamous NSCLC
II Combined to durvalumab KRAS mutant 76 PFS Not yet open NCT03004105
II Combined to MK-2206 Advanced NSCLC
334* 8-week DCR Ongoing, not recruiting
Molecular Profiling and Targeted Therapy
600 Feasibilit y of Molecula r Profiling and Targeted Therapy
II Combine to TXT
(National Lung Matrix Trial)
II High Throughput Genome Analysis as a Therapeutic Decision Tool
III Combined to TXT Second-line
- KRAS mutant
PFS Ongoing, not recruiting
AEs: incidence of adverse events; DCR: disease control rate; DLT: dose-limiting toxicity; G: grade; MTD: maximum tolerated dose; NSCLC: non-small cell lung cancer; ORR: objective response rate; PEM: pemetrexed; PFS: progression-free survival; PTX: paclitaxel; RP2D: recommended phase II dose; TXT: docetaxel; WT: wildtype; *multi-arm trial: overall population enrolled – www.clinicaltrials.gov [Last access 10 Jan 2017]
Papers of special note have been highlighted as either of interest (•) or of considerable interest
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55.Dean E, Steele N, H. Arkenau H, et al. SELECT-3: A phase I study of selumetinib in combination with platinum doublet chemotherapy for advanced NSCLC in the first-line setting. Annals of Oncology 2016;27 (6): 416-454
56.Nicholas GA, Goffin JR, Laurie SA, et al. A phase Ib study of selumetinib in patients (pts) with previously untreated metastatic Non-Small Cell Lung Cancer (NSCLC) receiving standard chemotherapy: NCIC Clinical Trials Group IND.215. NCT01783197. J Clin Oncol 2015; 33 (suppl; abstr 8046)
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59.Hainsworth JD, Cebotaru CL, Kanarev V, et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 2010; 5: 1630–36
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61.Janne PA, Ghiorghiu DC, Smith PD, et al. SELECT-4: Phase I dose escalation trial of selumetinib (AZD6244, ARRY-142886) in combination with durvalumab (MEDI4736) in patients with advanced solid tumors. J Clin Oncol 2016; 34 (suppl; abstr TPS2607)
• Phase II trial evaluated the efficacy and safety of 100 mg selumetinib free-base suspension twice daily versus pemetrexed as second- or third-line treatment: selumetinib did not demonstrate superiority to pemetrexed in terms of efficacy with a median PFS (primary end point)
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• Prospective randomised phase II trial evaluated the efficacy and safety of selumetinib in combination with docetaxel as second-line treatment for KRAS-mutated NSCLC patients: no significant difference between two groups in the median OS (primary end point), but significant improvements in PFS, ORR, and patient-reported outcomes with the combination.
63.Janne PA, Smith I, McWalter G, et al. Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. Br J Cancer 2015; 14;113(2):199-203
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•• The eagerly awaited first prospective phase III trial (SELECT-1) in KRAS-mutant NSCLC, evaluating selumetinib plus docetaxel versus docetaxel alone as second-line treatment, has failed to meet its primary endpoint of improvement in PFS
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